title: Structural insights of SIR2rp3 proteins as promising biotargets to fight against Chagas disease and leishmaniasis.
abstract: Trypanosoma cruzi and Leishmania spp. are protozoan pathogens responsible for Chagas disease and leishmaniasis, respectively. Current therapies rely only on a very small number of drugs, most of them are inadequate because of their severe host toxicity or drug-resistance phenomena. In order to find therapeutic alternatives, the identification of new biotargets is highly desired. In this study, homology modelling, docking and molecular dynamics simulations have been used to generate robust 3D models of NAD(+)-dependent deacetylases from Trypanosoma and Leishmania spp., known as SIR2rp3, whose structures have never been described before. Molecular docking of known inhibitors revealed strong analogies with the mitochondrial human SIRT5 in terms of binding mode and interaction strength. On the other hand, by extending the analysis to the channel rims, regions of difference between host and parasitic targets, useful for future selective drug design projects, were pointed out.
authors.affiliation: Pharmacochemistry and Phytochemistry & Bioactive Natural Products, School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, CH-1211 Geneva 4, Switzerland.
authors.forename: Lionel
authors.initials: L
authors.lastname: Sacconnay
authors.forename: Despina
authors.initials: D
authors.lastname: Smirlis
authors.forename: Emerson Ferreira
authors.initials: EF
authors.lastname: Queiroz
authors.forename: Jean L
authors.initials: JL
authors.lastname: Wolfender
authors.forename: Milena Botelho Perreira
authors.initials: MB
authors.lastname: Soares
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Carrupt
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nurisso
mesh_terms: D000595:Amino Acid Sequence; D014355:Chagas Disease; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007896:Leishmaniasis; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011487:Protein Conformation; D016415:Sequence Alignment; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000737:chemistry; D014349:Trypanosoma cruzi / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; C508544:SIRT5 protein, human; D056565:Sirtuin 2; D037761:Sirtuins